Sphincters are circular groups of smooth muscle that control the orifices of hollow organs. Sphincters present throughout the gastrointestinal (GI) tract control the passage of materials through this system of the body. When constricted, the sphincters close orifices leading to the hollow organs, such as the stomach, intestine, anus, etc. In order for the sphincter to open, the muscles must relax.
The sphincter that closes the anus (sphincter ani) consists of two sphincter muscle groups. The external anal sphincter is a thin flat plane of striated muscle fibers adherent to the integument surrounding the margin of the anus. The internal anal sphincter (IAS) is a ring of smooth muscle which surrounds the lower extremity of the rectum and is formed by an aggregation of the involuntary circular fibers of the intestine. Inflammation locally may cause sphincter spasm and pain. Thus, dilation of the veins in the anorectal area results in the condition known as hemorrhoids. Frequently, the hemorrhoidal condition is accompanied by bleeding, thrombosis, inflammation, and pain around the area of the rectum. The pain associated with hemorrhoids is due primarily to the inflammation adjacent to the anal sphincter.
Anal sphincter spasm is a condition in which the muscles of the internal anal sphincter are under abnormal tension. The strong contractions of the internal anal sphincter associated with sphincter spasm often give rise to painful linear ulcers or crack-like sores, known as rectal fissures, on the margin of the anus. Anal sphincter spasm is also considered a cause of the pain following rectal surgery or thrombosed hemorrhoids.
Current treatments of rectal fissures are directed at relieving sphincter spasm and include dilatation (under anesthesia) or cutting a part of the sphincter (lateral internal sphincterotomy). Applications of heat, cold, witch hazel, topical anesthetics, topical steroids, stool softeners, and bed rest have also been prescribed to treat rectal pain. However, none of these approaches significantly modifies the sphincter spasm itself.
A known moderator of sphincter tone is nitric oxide (NO). Nitric oxide has been shown to bring about a concentration-dependent reduction in the resting tension of internal sphincter smooth muscle strips in vitro (Rattan et al., Am. J. Physiol. 262:G107-112 (1992)). It has also been shown that L-arginine acts as a competitive inhibitor of compounds that block the action of NO production. NO has also been shown to mediate adaptive relaxation of other sphincters in the gastrointestinal tract including the lower esophageal sphincter (Conklin et al., Gastroenterology 104:1439-1444 (1993); Tottrup et al., Br. J. Pharmacol. 104:113-116 (1991)), pyloric sphincter (Bayguinov et al., Am. J. Physiol. 264:G975-983 (1993), sphincter of Oddi (Mourelle et al., Gastroenterology 105:1299-1305 (1993)), and the ileocolic sphincter (Ward et al., Br. J. Pharmacol. 105:776-782 (1992)). It is thought that NO or NO-like substances serve as important control mechanisms for the general phenomenon of gastrointestinal adaptive relaxation.
Currently there is no safe, effective, topical treatment available to treat patients suffering from spasms of sphincters located in the GI tract. Direct administration of NO gas is not a desirable method to induce sphincter relaxation because NO binds to hemoglobin and reduces oxygen transport to tissues throughout the body. In addition, NO is an unstable compound and has a short half life. High doses of NO gas would therefore be required; however, high doses of NO are cytotoxic.
Topical preparations of glycerol trinitrate have been examined as mediators of anal sphincter tone (Loder et al., Br. J. Surgery 81:1386-1389 (1994)). However side effects, such as headaches, were observed in the test patients. Esophageal spasm has also been treated with systemic application of nitroglycerin and long-lasting nitrates (Swamy et al., Gastroenterology 72:23-27 (1977)). However, the systemic use of these smooth muscle dilators may yield unwanted vascular effects.